The research training program will develop the skills of a postdoctoral candidate in the areas of cancer biology and genetic epidemiology. The candidate aspires to become an independent researcher in the field of genetic epidemiology to investigate and prevent cancer and other chronic diseases. The candidate will take courses and attend seminars related to biostatistics, cancer biology, genetic epidemiology and epigenetics. The specific research project the candidate will lead involves investigating if genetic predisposition to obesity modifies breast cancer risk in female BRCA1 and BRCA2 mutation carriers. The risk of breast cancer is high among female carriers of mutations in the BRCA1 and BRCA2 genes. However, there is high inter-individual variance with regard to breast cancer risk among BRCA1/2 carriers. Classes of BRCA1/2 mutations (e.g., loss of function or partially preserved normal function), the location of the BRCA1/2 mutations ("breast cancer cluster region'" or "ovarian cancer cluster region"), and other genetic and environmental factors have been shown to modify breast cancer risk in BRCA1/2 carriers. Obesity is a modifiable risk factor that has been associated with increased breast cancer risk in postmenopausal women. The research proposed will address three specific aims. Aim 1 will determine if genetic susceptibility to obesity modifies breast cancer risk in a large sample of BRCA1/2 carriers. Aim 2 will determine if the class of BRCA1/2 mutations and location of BRCA1/2 mutations interact with genetic susceptibility to obesity with regard to breast cancer risk. Aim 3 will determine if genetic susceptibility to obesity differentially increases the risk of estrogen receptor positive or estrogen receptor negative breast cancer. A retrospective cohort study design will be used to address these aims. Female participants were recruited through research clinics and all are screened for BRCA1/2 mutations. The cohort to be included in the proposed study will comprise female BRCA1/2 carriers, 18+ years old, free from any cancer before ascertainment, and free from breast cancer within 5-years and ovarian cancer within 3-years of ascertainment. Participants have been genotyped for variants within obesity susceptibility genes that were identified through genome-wide association studies. A cumulative obesity susceptibility score will be created for each participant by summing the number of risk alleles carried. In addition, haplotype associations will be conducted for each obesity susceptibility loci. Cox proportional hazard models, using a weighted approach to account for the sampling of high-risk women, will be used for the statistical analyses. The research proposed has the potential to identify an important modifier of breast cancer in BRCA1/2 carriers that can be target through energetic interventions that influence energy balance. PUBLIC HEALTH RELEVANCE: Female carriers of BRCA1 and BRCA2 mutations have an increased risk of breast cancer;however, there is a high inter-individual variance in breast cancer risk among BRCA1/2 carriers. The proposed research will investigate if genetic susceptibility to obesity modifies breast cancer risk in BRCA1/2 carriers. This study may identify an important breast cancer risk factor for BRCA1/2 carriers, which can potentially be targeted through energetic interventions.